Modern organic chemists have as one goal the development of new synthetic routes for the controlled, efficient production of asymmetric compounds. Saturated carbon atoms, constituting the backbone of most organic compounds, are attached to adjacent carbon atoms through a tetrahedral arrangement of chemical bonds. If the four bonds are to different atoms or groups, the central carbon provides a chiral, or asymmetric, center and the compound therefore may have the ability to exist in two mirror image, or enantiomeric, forms. It is crucial when synthetic organic chemists attempt to prepare these asymmetric compounds to have a means to produce the desired enantiomer because compounds of the wrong enantiomeric form often lack desirable biological, physical or chemical properties.
A particularly attractive approach to the synthesis of optically active compounds is the catalytic asymmetric hydrogenation of unsaturated substrates. This approach is highly efficient because the only reagent is hydrogen gas, which is easily removed from the product after the reaction is complete. Such hydrogenations are carried out using a small amount of a metal complex typically bearing a chiral diphosphine ligand. In the vast majority of cases the metal atom in such catalysts is rhodium or ruthenium. Conventional wisdom dictates that the chelating diphosphine ligand should be highly rigid to effectively control the course of the hydrogenation. Two highly successful examples of rigid diphosphine ligands are BINAP [Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345] and the DuPHOS ligands [Burk, M. J. Chemtracts Org. Chem. 1998, 11, 787].
One class of unsaturated substrate where asymmetric hydrogenation has had limited success are the 3-alkylidenelactams. A single report describes the use of a ruthenium catalyst bearing a BINAP ligand to hydrogenate a series of 3-alkylidene-2-piperidones [Chung, J. Y. L. et. al. Tetrahedron Lett. 1995, 36, 739]. The selectivity of this process was limited for simple alkylidene derivatives but could be enhanced by introducing a functionalized alkylidene side-chain to provide an “internal ligand effect”.
The use of 2,4-bis(diphenylphosphino)pentane (BDPP) ligands has been described but is not expected to impart enantioselectivity. This is because these ligands lack structural rigidity. It has been noted that, because of their flexibility, four conformers of a six-membered chelate ring containing metal-BDPP are possible, two of which are achiral chair conformations with the phenyl rings in an achiral array [MacNeil, P. A. et. al. J. Am. Chem. Soc. 1981, 103, 2273; Bakos, J. et. al. J. Organometal. Chem. 1989, 370, 263]. Thus the use of an iridium-BDPP catalyst to accomplish a challenging enantioselective hydrogenation of a C═C bond would not have been predicted by one skilled in the art. The particular iridium-BDPP catalyst utilized in the Applicants' process was previously studied as a potential catalyst for the hydrogenation of the C═N bond of imines; however, no enantioselectivity was observed unless the catalyst was adsorbed onto an insoluble clay support to provide additional rigidity [Margalef-Catala, R. et. al. Tetrahedron Asymm. 2000, 11, 1469].
Compounds disclosed in WO 00/35451 and similar publications are modulators of the CCR-3 receptor. Several of the compounds disclosed are prepared using 3-substituted-2-piperidones.
A need clearly exists for a process for the asymmetric hydrogenation of 3-alkylidenelactams which is practical, general, and highly enantioselective. The present invention provides such a process and affords 3-substituted lactams in a desired enantiomeric form. Other objects and advantages of the invention will become apparent to those skilled in the art upon reference to the detailed description, which hereinafter follows.